DESCRIPTION (From the applicant's abstract): Alzheimer's disease is a devastating neurodegenerative disease that afflicts over 4 million people in the United States. Two defining pathological features of the disease are extracellular senile plaques and intraneuronal fibrillary tangles, both abnormal features found in the brain of patients upon autopsy. The senile plaques consist of a proteinaceous amyloid deposit surrounded by degenerating neurites. The predominant protein component of the amyloid deposit is beta-amyloid (Abeta), a 4 kDa peptide derived from a much larger transmembrane precursor protein. Abeta deposits are fibrillar, with a diameter of 5-10 nm and a cross-beta structural motif. Mounting in vitro and transgenic mouse data support the hypothesis that Abeta, and more specifically, aggregated (fibrillar) Abeta, is neurotoxic and thus likely plays an essential role in the onset and/or progression of Alzheimer's pathology. This hypothesis leads to a proposed strategy for therapeutic intervention: compounds which can interfere with assembly of Abeta monomer into toxic fibrils should provide protection from Abeta toxicity. Abeta is an amphiphilic self-associating peptide whose sequence is known. To self-associate, Abeta must be able to "recognize" other copies of itself. This leads to the intriguing possibility that molecules which borrow partial sequences from Abeta could also associate specifically with, or recognize, Abeta. Such sequences would be useful as means to target Abeta. These recognition elements could then be coupled to elements that were capable of disrupting Abeta aggregation. The hybrid compounds, containing both recognition and disrupting functionality, could potentially prevent Abeta neurotoxicity. In preliminary work, four such hybrid compounds were synthesized. These compounds disrupted Abeta aggregation and protected cells in vitro from Abeta toxicity. In the proposed research, this modular design strategy is explored in much greater depth. A library of peptidyl and organopeptidyl compounds will be synthesized, drawing on knowledge of the amino acids in Abeta that are responsible for the Abeta-Abeta interaction. Those compounds which prove to be effective recognition elements will be coupled to a palette of peptide- or saccharide-based disrupting elements. Such compounds will be evaluated extensively for their effect on Abeta aggregation and their ability to interfere with Abeta cellular toxicity. By repeated rounds of synthesis and evaluation, compounds which are highly effective at interfering with Abeta aggregation will be generated. Such compounds may serve as useful probes of the role of Abeta aggregation in neurotoxicity and may provide leads for developing clinically effective therapies for the treatment of Alzheimer's disease.